1. Field
The invention is in the medical field of radiation oncology, specifically boron neutron capture therapy for cancer, usually spoken of as BNCT. It is concerned with accelerator-based apparatus for, and with methods of, producing epithermal neutron spectra for application to humans and to animals in general.
2. State of the Art
BNCT is a still experimental, therapeutic, binary modality for treatment of certain types of refractory malignancies. The current area of research interest is Glioblastoma Multiforme, a primary brain tumor. Procedurally, boron-10, which has a particularly large cross section for capture of "thermal" neutrons, i.e., neutrons having energies less than 0.5 electron volts (eV), is preferentially introduced into the malignant tissue by administration of a suitable boronated pharmaceutical. A thermal neutron field is then generated within such tissue by application thereto of an externally-produced neutron beam, the objective being the selective destruction of the malignant tissue by energetic, secondary, charged particles, specifically helium-4 and lithium-7 ions, that result from neutron capture interactions in the boron-10. The average total energy of such ions is 2.35 million electron volts (MeV). This energy is deposited along charged particle paths that are comparable in dimensions to the cellular dimensions of the malignant tissue, thereby offering the possibility of cancer cell inactivation with only limited damage to nearby healthy tissue, which, ideally, contains no boron.
Until recently, human applications of BNCT were limited to some early (in the 1950s) trials in the United States and more recently to an extensive series of treatments conducted over a period of approximately the last twenty years in Japan. The early trials in the U.S. were unsuccessful for a variety of reasons. The more recent applications of BNCT in Japan have been much more successful, primarily because of the development and use of better boronated pharmaceuticals. This has led to a worldwide resurgence of interest in BNCT research, and to the resumption, in 1994 of clinical trials in the USA.
Most BNCT research efforts have been strongly influenced by the recognition that an "epithermal" neutron beam (a beam comprised primarily of neutrons whose energies fall within the energy range between 0.5 and 10,000 eV) should ultimately prove to be optimal for human clinical applications. Such a beam will have an advantage over the relatively low energy, "thermal" neutron beams currently used in Japan for application to human brain tumors. This realization is a result of the known physical fact that "epithermal" neutrons will penetrate a few centimeters into tissue before forming a neutron flux peak, whereas "thermal" neutrons do not have nearly as much penetrating power. Thus, if a beam of epithermal neutrons can be produced that is not, in itself, capable of causing significant biological damage, it will offer a safe and effective way of applying BNCT for deep-seated malignancies.
So far, however, only nuclear reactors have produced epithermal neutron beams useful for BNCT. Neutrons leaking out of one side of an active reactor core are directed into and through a filtering (allowing neutrons of a certain energy range to pass through) and moderating (reducing energy of all neutrons to a lower average level) region containing materials that cause, via neutron scattering and absorption, the so-derived, very high energy neutron beam to assume a spectrum whose energy distribution is strongly peaked in the desired epithermal energy range. The epithermal neutron beam that emerges from the filtering and moderating region is passed through gamma ray shielding material before application.
Materials which have proven suitable for use in the filtering and moderating region of nuclear-reactor-based, epithermal neutron facilities for BNCT are various combinations of metallic aluminum, heavy water (D.sub.2 O), sulfur, aluminum trifluoride (AlF.sub.3), alumina (Al.sub.2 O.sub.3), titanium, and vanadium, as well as a mixture of metallic aluminum and the material Teflon.RTM.. Gamma shielding materials that have been used are lead, bismuth, and liquid argon.
Epithermal neutron beams that have been produced by reactor-based facilities have epithermal neutron flux intensities in the range of 2.0.times.10.sup.8 neutrons per square centimeter per second (n/cm.sup.2 /s) to 1.0.times.10.sup.10 n/cm.sup.2 /s.
It has been recognized that an epithermal neutron beam for BNCT use should have any neutron flux intensity above 10,000 eV suppressed to a level that is roughly two orders of magnitude (factors of 10) below the intensity of the flux in the useful epithermal energy range. This serves to protect a patient from normal tissue damage caused by non-selective, proton-recoil interactions that occur in hydrogenous tissue when such tissue is exposed to neutron radiation. Also, it has been recognized that proton recoil interactions are non-selective and that such interactions induced by neutrons having energies significantly above the upper cutoff of the epithermal energy range are particularly damaging to normal tissue and should be minimized to the extent possible by careful neutron beam design to suppress the high-energy spectral component. Also, it has been recognized as important to suppress any "thermal" neutron component of an epithermal neutron beam, since it can cause significant surface tissue damage. "Thermal" neutrons are generally suppressed in reactor-based, epithermal neutron beams by inclusion of small amounts of cadmium, lithium, and boron in various locations within and around the epithermal neutron filtering regions.
Some nuclear-reactor-based, epithermal neutron beam facilities have been constructed and are in operation. It is expected that these facilities will continue to be used extensively in BNCT research and probably for initial human clinical trials of epithermal neutron BNCT in the United States. However, there has also been a great deal of interest in the development of a practical accelerator-based source of epithermal neutrons for BNCT. Particle accelerators are already used routinely for various other types of cancer radiotherapy and are a well-accepted technology in the clinical medicine community. Designs for accelerator-based neutron sources for BNCT that feature the use of proton beams impinging on either lithium or beryllium targets have been proposed in the literature and, in some cases, low-intensity prototypes have been constructed. In these concepts, protons having energies of approximately 2.5 MeV induce neutron-producing interactions in target materials. The resultant neutrons are then filtered and moderated into the desirable epithermal energy range using materials and techniques that are to some extent similar to those employed to produce reactor-based epithermal neutron beams. These proton devices have, however, proven to be difficult to scale to the output neutron beam intensities necessary for clinical application of BNCT. Because of problems associated with production of a proton beam of sufficient intensity and with removing the rather high level (50-250 kilowatts) of waste heat that is generated within the accelerator target, a sufficiently intense accelerator-based source of epithermal neutrons that are of practical utility for BNCT has yet to be constructed.
It has been well-known for years that neutrons can also be produced using a particle accelerator via a two-stage process by which an electron beam of sufficient energy is directed upon a target material having a relatively high atomic number (e.g. tungsten), and the bremsstrahlung photon radiation thus produced is directed into a material or a combination of materials that exhibit a high cross section for photoneutron production. Such a particle accelerator has been used to produce neutrons for a variety of non-medical purposes. In such applications, however, relatively high (tens of MeV) electron beam energies are used in order to obtain a sufficiently high neutron yield per original incident electron. The photoneutrons that are thus produced inherently have energies that are much too high for BNCT purposes. So much filtering would be required for these high-energy sources that sufficient neutron flux intensities within the required epithermal energy could not reasonably be obtained while simultaneously suppressing the higher than epithermal flux to a radiobiologically satisfactory level.
The use of a relatively low electron beam energy (8 to 12 MeV) was shown to offer a potentially-useful approach by a solely mathematical study conducted by two of the present applicants and published in abstract form in November 1992. This study was based on the contemplated use of an accelerator-based device capable of producing a filtered photoneutron beam having a flux intensity about 5 to 10 times lower than what we, in accordance with the present invention, now regard and what has historically been accepted in the relevant scientific community as the desired level (a minimum of 1.0.times.10.sup.9 n/cm.sup.2 /sec) for practical BNCT.
Nothing in the known prior art suggests that such a minimum level of flux intensity for a delimited beam of epithermal neutrons can be obtained by use of an electron accelerator. This was not shown to be obtainable by the hereinbefore-referred-to, solely mathematical study published in November 1992 in abstract form, nor has it been known to be obtainable by any electron radiation impinged on photon producing target material. Moreover, the specific filtering and moderating materials, and the relative proportions thereof, have not been suggested, except as previously indicated with respect to nuclear-reactor based systems.